Abstract
Pseudomonas aeruginosa exotoxin A (PEA) causes severe hepatotoxicity in experimental animals and is useful in investigations of immune-mediated liver injury. However, strain differences in the sensitivity to PEA-induced hepatotoxicity in rats remains be elucidated. In this study, we determined the severity of PEA-induced hepatotoxicity in six genetically different rat strains. Male LE (Long Evans), Wistar, F344, WKY, BN/SsN and LEW rats were administered a single intravenous injection of PEA (20 μg/kg). Significantly elevated serum ALT and AST levels, massive necrosis and hemorrhage, and numerous TUNEL-positive hepatocytes were observed in BN/SsN rats. In contrast, low levels of ALT and AST as well as mild changes in liver histopathology were observed in Wistar and F344 rats. Moderate levels of hepatic injuries were observed in LE, WKY, and LEW rats. Pro-inflammatory cytokines including TNF-α, IL-2 and IL-6 serum levels were markedly increased in BN/SsN rats compared to Wistar and F344 rats. However, the hepatic levels of low density lipoprotein receptor-related protein (LRP), which functions as the PEA receptor, were not significantly different in each strain. Taken together, we suggest that BN/SsN is the most sensitive rat strain, whereas Wistar and F344 were the most resistant rat strains to PEA-induced liver damage. The different genetic background of rat strains plays an important role in the susceptibility to PEA-induced epatotoxicity that may depend on immune-regulation but not LRP receptor levels.
Highlights
Pseudomonas aeruginosa is an opportunistic, non-fermentative, Gram-negative rod bacterium.P. aeruginosa has emerged as a major infectious disease agent, in patients with burn injuries or cystic fibrosis [1,2]
We firstly evaluated the hepatic expression of lipoprotein receptor-related protein (LRP) in different rat strains
The present study showed that Brown Norway (BN)/SsN rats had severe liver injury in of response
Summary
P. aeruginosa has emerged as a major infectious disease agent, in patients with burn injuries or cystic fibrosis [1,2]. Several virulence factors, such as P. aeruginosa exotoxin A (PEA) and exoenzyme S, are involved in the disease caused by this bacterium [3]. The decreased expression of LRP may enhance macrophage and hepatocyte cell-line resistance to PEA induced cytotoxicity [5,6]. Laithwaite and collaborators reported that increased PEA sensitivity in BNL 1ME A7R.1 transformed hepatocytes was associated with increased functional cell surface LRP expression [7]
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